In spite of the extensive use of oral anticoagulants in medicine, their mechanism of action is unknown. It has been assumed that the coumarin anticoagulants, because of structural similarity, compete with vitamin K for an active site, but recent evidence suggests that the locus of action of anticoagulants may be on the metabolism of vitamin K. Warfarin causes the accumulation of phylloquinone oxide, a metabolite of vitamin K1, in rat liver. The oxide is a competitive inhibitor of vitamin K1 in anticoagulant treated animals. I propose to further investigate the effect of anticoagulants on the metabolism of vitamin K and to determine if the accumulation of the oxide is the basis for warfarin action. Anticoagulant-treated animals will be injected with various doses of radioactive vitamin K1 and the stimulation of prothrombin synthesis will be correlated with the relative amounts of vitamin K1 and phylloquinone oxide in the livers. The metabolism of labelled vitamin K1 and phylloquinone oxide will be studied in rats which are genetically resistant to warfarin to determine if the resistance is accompanied by a loss of the effect of warfarin on the metabolism of the vitamin and oxide. The effect of anticoagulants on the metabolism of the cis isomer of vitamin K1, which has little or no vitamin K activity, will also be examined. Sex hormones have a marked effect on clotting protein synthesis. The interaction of sex hormones and anticoagulants on vitamin K metabolism and prothrombin synthesis will be studied.